1. Field of the Invention
The present invention identifies a new fibroblast-derived mitogen called plasminogen-like growth actor (PLGF) with activity on melanocytes, epithelial and endothelial cells. In particular, the present invention relates to the purification, molecular cloning and recombinant expression of PLGF which bears strong sequence homology to HGF but yet exhibits broad target cell specificity whose pattern is distinct from HGF and any other known growth factor.
2. Background of the Invention
Growth factors are widely believed to play important roles in normal development and wound healing. R. James and R. A. Bradshaw, Annu. Rev. Biochem. 53, 259 (1984); T. F. Deuel, Annu. Rev. Cell Biol. 3, 443 (1987); A. Barbul, E. Pines, M. Caldwell, T. K. Hunt, Eds., Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. Progress in Clinical and Biological Research Vol 266 (Alan R. Liss, New York, 1988) Their abnormal expression has been implicated in neoplasia as well as a variety of other proliferative disorders. (M. B. Sporn and E. D. Harris, Jr., AM. J. Med. 70, 1231 (1981); A. S. Goustin, E. B. Leof, G. D. Shipley, H. L. Moses, Cancer Res. 46, 1015 (1986); M. B. Sporn, A. B. Roberts, J. Clin. Invest. 78, 329 (1986); R. Ross, New. Engl. J. Med. 314, 488 (1986). Accumulating evidence indicates that mesenchymal interactions presumably mediated by diffusible substances have a major impact on epithelial cell proliferation (G. R. Cunha, L. W. K. Chung, J. M. Shannon, O. Taguchi & H. Fujii, Recent Prog. Hormone Res. 39, 559 (1983); R. H. Sawyer and J. F. Fallow, Eds., Epithelial-Mesenchymal Interaction During Development (Praegerm New York, 1983); S. L. Schor, A. M. Howell & D. Crowther, Exp. Cell Biol. 55, 11 (1987), yet there is relatively little knowledge of such stromal cell effectors. Systematic efforts to isolate and characterize epithelial-acting mitogens produced by stromal cells have led to the discovery of keratinocyte growth factor (KGF), a new member of the FGF family, specific for epithelial cells. (J. S. Rubin, H. Finch, P. W. Taylor, W. G. Rudikoff & S. A. Aaronson, Proc. Natl. Acad. Sci. U.S.A. 86, 802-806 (1989); P. W. Finch et al., Science 245, 752 (1989).
It is clear that a need exists for identifying new epithelial cell mitogenic activities produced by stromal fibroblasts. The present invention describes the purification and molecular cloning of a new growth factor called PLGF derived from stromal fibroblasts possessing a novel spectrum of target cells and its unexpected homology to other proteins involved in growth and tissue remodeling.